Inflammatory cytokine interleukin-1 (IL-1) performs multiple functions in the central nervous system (CNS). Two receptors have been identified for IL-1: the type I IL-1 receptor (IL-1R1) which is generally accepted as the receptor through which IL-1 activates cellular signaling;and the type II IL-1 receptor (IL-1R2) which serves as a decoy receptor. IL-1R1 is thought to mediate most, if not all, IL-1-induced effects. Several recent studies, however, show that IL-1- induced effects including its influence on brain tissue damage after cerebral ischemia, activation of JNK signaling pathway, and repression of synaptrophin mRNA expression persist in IL-1R1 knockout animals, suggesting the existence of a heretofore unidentified receptor for IL-1. Recently, we found that IL-1R1 gene contains an internal promoter which drives the transcription of a shortened IL-1R1 mRNA. This mRNA is the template for the production of an IL-1 receptor protein that is identical with IL-1R1 at the C-terminus, but with a shorter extracellular domain at the N-terminus. This receptor retains all the intracellular signaling machinery of IL-1R1. We have termed this molecule IL-1R3. Our preliminary results show that the mRNA and protein for IL-1R3 are expressed in normal and the two strains of commercially available IL-1R1 knockout animals. In addition, IL-1[unreadable] binds specifically to IL-1R3 and causes an increase in voltage-gated potassium current in neurons. On the other hand, IL-1[unreadable] stimulation of IL-1R3 does not activate NF-kB, the classical IL-1 signaling pathway. We propose that IL- 1R3 is the IL-1 receptor that accounts for the currently unexplained effects of IL-1 in the brain. In this application, we will investigate: 1) interaction between IL-1 and IL-1R3, 2) the role of IL- 1R3 in IL-1-induced activation of signal transduction pathways, and 3) the influence of IL-1R3 on NMDA-induced acute neurotoxicity. The results of this application should fill, at least in part, the apparent gap in our current knowledge on IL-1/IL-1 receptor interaction and potentially lead to discoveries of specific agonists or antagonists for IL-1R3, which could have significant clinical applications. PUBLIC HEALTH RELEVANCE: This study investigates a new IL-1 receptor that we recently discovered. IL-1 mediates many immunological, neuroimmunological, and neurophysiological activities in the brain. Currently, the type I IL-1 receptor (IL-1R1) is the only receptor known that mediates IL-1 signaling. We found that the new IL-1 receptor (IL-1R3) has the potential to account for many currently unexplained IL-1 effects. The results of this study will fill an apparent gap in IL-1 biology and potentially generate clinically useful molecules for IL-1 related brain disorders.